The present invention relates to the pharmacological treatment of various secondary neurological, behavioral and cognitive symptoms or disorders emanating out of brain or systemic impairments, i.e., primary impairments.
The secondary symptoms and disorders include as non-limiting examples, tic and behavioral disorders including Tourette""s syndrome and severe non-Tourette""s motor or vocal tics; Posttraumatic Stress Disorder (PTSD); atypical attention deficit disorder with or without hyperactivity; frontal lobe defects of executive function; oscillopsia; self-mutilation; violence or rage such as in intermittent explosive disorder; asocial behavior; sexual disorders (including gender choice difficulties or hyposexuality); psychological (psychosis, violence, and confusion) and motor symptoms of Huntington""s Disease (Huntington""s Chorea); fatigue, exhaustion, sleep problems, and pain of Chronic Fatigue Syndrome with or without Fibromyalgia; psychosis with multiple hallucinations and delusions secondary to brain injury; opiate narcotic addiction; Sick Building Syndrome (SBS); Gulf War Syndrome (GWS); Reflex Sympathetic Dystophy Syndrome (RSDS), also known as Complex Regional Pain Syndrome (CRPS); Retinitis Pigmentosa (RP); Cerebral Palsy; Torticollis; Dystonia; Dyskinesia; Institutionalization Syndrome, also known as Concentration Camp Syndrome or Survivor Syndrome; and Dementia, Alzheimer""s dementia or non-Alzheimer""s dementia. It should be noted that a symptom is a single manifestation while a disorder involves more than one symptom or a cluster of symptoms.
The symptoms and disorders are secondary to the primary impairments and emanate from neurological diseases or brain lesions including Tourette""s Disease, non-Tourette""s tic disorders, Asperger""s Syndrome, temporal lobe or other focal epilepsy, Huntington""s Disease, brain tumors or cysts, systemic lupus erythematosus, viral infections and their resulting neurological injuries, and various psychological disorders such as multiple personality disorder, borderline personality, organic psychosis, and severe traumatic experiences.
Gilles De La Tourette""s syndrome is characterized by motor and vocal tics, i.e., involuntary, sudden, rapid, recurrent, nonrhythmic, stereotyped motor movement or vocalization. Some researchers hypothesize that there is a dysregulation in presynaptic dopamine function in Tourette""s disorder (T.D.) and tics can be exacerbated by drugs that enhance synaptic dopamine function. R. T. Madison et al., Am. J. Psychiatry 152(9):1359-1361, 1995. Pharmacologic therapy has included low doses of dopamine-2 blockers and dopamine-antagonists including haloperidol, risperidone, or pimozide. T. M. Hyde et al., JAMA 273: 498-501, 1995. A problem with this dopamine-2 blockade is that this may often produce decreased attention, hyperactivity, dysphoria, and extrapyramidal symptoms in T.D. patients. Furthermore, if T.D. patients are treated with dopamine-2 stimulating analeptics (such as methylphenidate, dextroamphetamine, or pemoline) for their cognitive, attention, and hyperactivity problems, their motor and vocal tics are intensified. Non-Tourette""s tic disorder most commonly arises out of previous analeptic treatment and persists after such treatment.
Dystonia is a neurological movement disorder characterized by involuntary muscle contractions which force certain parts of the body into abnormal, sometimes painful, movements or postures. Dystonia can affect any part of the body including the arms and legs, trunk, neck, eyelids, face or vocal cords. Dystonia is the third most common movement disorder after Parkinson""s Disease and Tremor, affecting more than 300,000 people in North America. Currently, no medication or therapy can prevent progression of Dystonia from happening. Dystonia will usually stabilize within five years of onset, but symptoms may fluctuate and stressful situations, anxiety or depression may make symptoms temporarily worse. Treatments currently available not only fail to cure this disorder but only moderately abate the symptoms of Dystonia.
One form of Dystonia is Torticollis which is a neurological movement disorder in which the muscles controlling the neck undergo repetitive or sustained contraction, causing the neck to involuntarily jerk, twist or rotate. The abdominal posture caused by Torticollis is often debilitating and painful. Torticollis most commonly begins between age 30-60, and it affects 83,000 people in the United States. There are three types of torticollis: tonic, sustained abnormal posture; clonic, jerky head movements; and mixed, a combination of tonic and clonic movements. Symptoms progress over two to five years and then remain steady, but may worsen during stressful times. There is no cure for Torticollis. The current treatment provides only temporary relief of symptoms for a short time period before new treatment is needed. Torticollis is also referred to as spasmodic wryneck, idiopathic cervical Dystonia, ICD, cervical Dystonia and spasmodic Torticollis.
Dyskinesia is the impairment of muscle movement, or lack of control over ordinary muscle movement. Typical dyskinetic movements are Chorea, rapid movements; or Dystonia, twisting movements, muscle cramps and unusual posturing. Lingual, facial and tardive dyskinesia is characterized by twitching of the face and tongue, and involuntary movements of the body and limbs. Dyskinesia tends to occur more in people with early onset of Parkinson""s disease (before 50 years old). There is no known cure for dyskenesia.
Posttraumatic Stress Disorder (PTSD) follows exposure to a traumatic experience involving actual or threatened death or injury or threat to the physical integrity of oneself or others. PTSD includes characteristic symptoms of reexperience, avoidance of stimuli associated with the trauma, and numbing of general responsiveness or hyperarousal (sleep difficulty, anger, difficulty concentrating, hypervigilance or exaggerated startle response) with clinically significant distress or impairment. Studies in the United States demonstrate that 5 to 6 percent of men and 10 to 14 percent of women had had PTSD at some time in their lives, making it the fourth most common psychiatric disorder. It has been established that PTSD is associated with organic changes in the limbic system. It has also been suggested that a kindling model or a model of a paroxysmal disorder is applicable to PTSD (S. Liper et al., Psychosomatics 27 (12): 849-854, 1986). In the kindling model (R. M. Post et al, Clin. Neuropharmacol. 2:25-42, 1977), cumulative bioelectric changes, especially in the limbic area and secondary to repeated biochemical or psychological stress, can result in abnormal limbic or neuronal sensitization and major psychiatric disturbances. Recent neuroanatomical studies have identified alterations in two major brain structuresxe2x80x94the amygdala and hippocampusxe2x80x94in patients with PTSD. The reactivity of the amygdala and anterior paralimbic region to trauma-related stimuli is increased, and the reactivity of the anterior cingulate and orbitofrontal areas decreased. These areas of the brain are involved in fear responses. Differences in hippocampal function and in memory processes presumed to be dependent on the hippocampus have been found, suggesting a neuroanatomical substrate for the intrusive recollections and other cognitive problems that characterize PTSD (R. Yehuda, N Engl J Med 346 (2): 108-113, 2002). The finding of shrinkage in the hippocampus suggests a loss of cell mass. The loss is not yet known, but may be due to the effects of heightened levels of cortisol, a steriod hormone secreted by the brain in response to emergencies, some researchers believe. Cortisol is a major means the body uses, with adrenaline, to arouse itself so quickly, but it can be toxic and damaging to the hippocampus (D. Goleman, Science, C3, Aug. 1, 1995). Pharmacologic therapy for stress disorders has included benzodiazepines (e.g., lorazepam, diazepam, clonazepam), beta adrenergic blockers and antiseizure medications such as carbamazepine and valproic acid. It has been suggested that PTSD can induce a long-lasting brainstem dysfunction resulting in loss of the normal inhibitory modulation of startle response (E. M. Omitz et al, Am. J. Psychiatry 146(7): 866-870, 1989), and clonidine has been used to decrease noradrenergic action and inhibit startle response. Nevertheless, no successful dramatic treatment of PTSD has been discovered for the severe, chronic cases of this crippling disorder. A number of articles describing current developments in PTSD appear in Psychiatric Annals 28:424-468, 1998.
A successor to Posttraumatic Stress Disorder (PTSD) is Institutionalization Syndrome or Concentration Camp Syndrome, also referred to as Survivor Syndrome, and related to War Neurosis. Concentration Camp Syndrome includes the symptoms associated with PTSD as well as additional symptoms such as psychiatric and social disorders, distortion, disturbance of memory such as amnesia, psychogenic amnesia, hyperamnesia and disturbances of consciousness. Due to complexity of disturbances involved in this syndrome, it has also been characterized as pervasive, depressive mood with morose behavior; chronic apprehension, paranoia including tendency to withdraw; insecurity and helplessness; social dysfunction including lack of interest, emotion or initiative; thoughts of death; psychosomatic stress; somatizing, ranging from rheumatic or neurologic pains and aches to psychosomatic diseases such as peptic ulcers, colitis, respiratory and cardio-vascular syndrome; hypertension; mental confusion; panic attacks; nightmares; anxiety, angry outbursts, agitation; or psychotic disturbances with delusional or semi-delusional symptomatology.
Multiple Personality Disorder is a Dissociative Disorder which includes the existence within the person of two or more distinct personalities which recurrently take full control. There is an extensive inability to recall personal information. Dissociative disorders may occur as acute responses to overwhelming trauma and are common in combat or disasters. There is probably also a relationship between seizures and these disorders. Devinsky et al., Neurology 39:835-840, 1989.
Borderline personality disorder is characterized by tumultuous interpersonal relationships, labile mood status, and behavioral dyscontrol. Self-mutilation and violent behavior can also be seen with this disorder. Carbamazepine, an anti-convulsant with preferential action on limbic foci, produced decrease in severity of behavioral dyscontrol (R. W. Cowdry et al., Arch. Gen. Psychiatry 45:111-119, 1988) but not in the other multiple symptoms.
Primary attention deficit hyperactivity disorder (ADHD) is characterized by developmentally inappropriate failures of attention, hyperactivity, cognitive function, and impulsivity. The ADHD syndrome is idiopathic (no known secondary cause such as brain injury, dementia or known metabolic disease), begins at birth or soon thereafter, and usually has a strong hereditary basis.
Violence or rage (intermittent explosive disorder) can also be categorized as an impulse control disorder. There is a loss of control grossly out of proportion to any precipitating psychosocial stresses. Disabling outbursts of rage and violent behavior can be related to chronic brain syndrome associated with irreversible CNS (central nervous system) lesions. Yudofsky et al., Am. J. Psychiatry 138:218-220, 1981. Disorders characterized by severe episodic dyscontrol can result from brain dysfunction, e.g., resulting from a failure of modulation of electrical disturbances in the limbic system (amygdala, hippocampus, hypothalamus), temporal lobe epilepsy (TLE), brain lesions or injuries which can have neurological side effects. Other brain dysfunction disorders include motor, personality, or behavior patterns arising from, e.g., neurological impairment in the brain, TLE, viral infections, neurotransmitter disorders, amino acid imbalance, brain tumors, chromosomal abnormalities, metabolic disorders including endocrine disorders, diabetes, and genetic disorders such as disease which involves several genes, and chromosomal disorders.
Dementia or chronic brain syndrome is defined as a group of symptoms involving progressive impairment of all aspects of brain function. Studies have concluded just over 1% of the population aged 65-74 suffer from Dementia, and as many as 47% of people over 85 suffer from some form of Dementia. More than half of the people diagnosed with Dementia are classified as having Dementia resulting from Alzheimer-type Dementia generally are expected to live eight years from diagnosis. Generally symptoms characterizing Dementia include memory impairment or loss; cognitive disturbances such as alexia, agraphia, aphasia, apraxia, agnosia; emotional disorders, such as depression, anxiety, aggression, apathy, flat affect or social withdrawal; sleep dysfunctions or disturbance; severe mental status fluctuation such as confusion, hallucinations, delusions, disorientation, hyperactivity or limited alertness. There is no known cure for Dementia. The current goal of treatment has been to control the symptoms of Dementia.
Temporal lobe lesions may be brain damage produced by injury, disease, viral infection, and surgery, and can produce disturbances characterized, e.g., by seizures, which can include, e.g., motor phenomena, impairment of external awareness, depersonalization, emotional changes, behavioral disturbances, psychosis, multiple cognitive disturbances, distortions or hallucinations of any of the five senses, and autonomic disturbances (gastrointestinal, cardiac, sweating, and headache symptoms among others). The symptoms can be severe and difficult to treat. The drugs used in treatment depend on the type of seizures and have included phenytoin, carbamazepine, valproic acid, phenobarbital, primidone, felbamate, gabapentin, and lamotrigine.
Various pharmacological approaches have been taken in treating the conditions described above. For example, a number of medications such as lithium, neuroleptics, anticonvulsants, buspirone and beta blockers have been used to reduce violent behaviors as a symptom, but there are no officially labeled treatments for violent behaviors. J. Fawcett, Psychiatric Annals 27(11):725, 1997. But, particularly when the symptoms are very severe, the standard pharmacological approaches to alleviate the symptoms of episodic dyscontrol are often unsuccessful.
Temporal lobe epilepsy poses particular problems which can include simple partial seizures that can be manifested by motor symptoms, sensory symptoms, or psychic symptoms including impairment of consciousness, dysphasia, dysmnesia, illusions, and hallucinations. Complex partial seizures include impaired consciousness and psychic symptoms. The drugs used in treatment depend on the type of seizures and have included phenytoin, carbamazepine, valproic acid, phenobarbital, primidone, felbamate, gabapentin, and lamotrigine.
Temporal lobe epilepsy (TLE), and other organic brain disorders may be associated with various sexual impairments. See, e.g., D. M. Bear, xe2x80x9cTemporal Lobe Epilepsyxe2x80x94A Syndrome of Sensory-Limbic Hyperconnectionxe2x80x9d, Cortex 15:357-84, 1979. The most common sexual effect of organic brain problems is a loss of sexual interest and drive (hyposexuality). Less often sexual preference changes can occur and rarely fetishistic, exhibitionistic, or sadomasochistic problems occur. Some patients also develop an obsessive concern about sex and sexual performance. Treatment for these sexual problems is poor with antiepileptic or psychiatric medications but at times has been altered by unilateral temporal lobe surgery, a rather heroic procedure that many, if not most, patients are unable to undergo.
Damage to frontal lobes can also impair the executive function, that is the ability to plan, initiate, organize, carry out, monitor, and correct one""s own behavior. W. W. Beatty and N. Monson, xe2x80x9cProblem Solving By Patients With Multiple Sclerosisxe2x80x9d, Journal of the International Neurological Society 2:134-140, 1996; V. Goel and P. Grafman, xe2x80x9cAre Frontal Lobes Involved With Planning Functions? Interpreting Data From the Tower of Hanoixe2x80x9d, Neuropsychologia 5:623-642, 1995.
Sexual abnormalities can be associated with epilepsy or other brain diseases. These include a loss of sexual interest and drive (hyposexuality); fetishistic, exhibitionistic, or sadomasochistic problems; sexual preference changes (homosexuality, transsexuality, or transvestism); obsessive interest in sex or sexual performance; or compulsive sexual activity. Homosexuality may become a problem for those patients who have difficulty accepting this change or who are under societal pressure. It has been long established that altered sexuality can result from various brain impairments including temporal lobe epilepsy. D. M. Bear, Cortex 15:357-384, 1979.
Another hereditary or genetic neurological disorder is RP, a chronic progressive deterioration of vision that begins usually at the age of 20-30 years and gradually leads to progressive loss of vision and finally blindness at the age of 40-50 years. A characteristic is that vision is particularly worse in poor light and color vision goes first. Approximately 1 in 3000 in the population suffer from inherited retinal degeneration. About one in 80 people carry a single copy of a recessive RP gene. There are no known treatments for RP at this time.
Huntington""s Disease (H.D.) is a relatively rare (6/10,000 in U.S. and Europe) fatal neurological disorder of a hereditary nature. It is an autosomal chromosome 4 dominant disorder with full penetrance (50% chance of all children of being affected) which usually begins between age 35-40 years and kills the patient in about 15 years with severe behavioral and neurological impairments in this morbid period. There are no successful treatments of these behavioral or neurological disorders of H.D. Neither gamma amino butyric acid (GABA) agonists (i.e., carbamazepine or valproic acid) nor antipsychotic medications repair the behavioral or neurological problems of H.D. in any satisfactory fashion.
Fibromyalgia (FM) and Chronic Fatigue Syndrome (CFS) are similar problems of unknown cause which lead to considerable suffering and debility over 6 months or more and often for many years. The incidence is approximately 250 per 100,000 for CFS and as high as 5% of the general medical population for FM. There are no reliably successful treatments and certainly no FDA approved treatments for these two disorders. The management of FMS involves a multidisciplinary approach including various medication which affect the central nervous system, and addressing each perpetuating factor, such as pain, lack of sleep, fatigue and muscle rigidity, separately. Medications are used along with a program of proper diet, life-style changes, mind work and body work. FM and CFS share in common severe fatigue, impaired concentration and memory, exercise intolerance, unrefreshing sleep, muscle and joint pain, malaise, and headaches. FM is differentiated from CFS by specific point pain spots in the muscles and CFS differs from FM by having a sore throat, tender cervical or axillary lymph nodes, variably elevated erythrocyte sedimentation rate, occasional low grade temperature, and a variety of immunologic or neuroendocrinologic test values (none of which are consistent or indicative of any known etiologic agent). See, e.g., K. Fukuda et al., Ann. Intern. Med. 121:953-959, 1994; A. L. Komaroff et al., Rev. Infect. Dis. 13(Suppl. 1):S8-11, 1991. Both are clearly different from a depressive diagnosis. A recent study by A. L. Komaroff et al., Am. J. Med. 101:281-290, 1996, showed marked impairment of the CFS patients vs. patients with hypertension, acute myocardial infarction, multiple sclerosis, NIDDM, diabetes, congestive heart failure, or depression. Moreover, the degree and pattern of impairment CFS was different from that seen in depression. This is also the case in Fibromyalgia. L. J. Kirmayer et al., Am. J. Psychiatry 145:950-954, 1988.
Gulf War Syndrome is a disorder of unknown etiology and affecting about 1% of all Gulf War veterans according to Defense Department research. One clue to the cause is that a number of those veterans affected never reached the Gulf War area but contracted the syndrome while training for the war in Europe. This suggests that various injections or protective vaccines may have had some etiological role. The symptoms of GWS are very similar to those of Fibromyalgia/Chronic Fatigue Syndrome with the addition of severe allergic complaints. According to the American Legion, symptoms may include: chronic fatigue, headache, muscle pain, sleep disturbance, neuropsychological signs or symptoms (such as memory loss or encephalopathy), and various allergic signs and symptoms including asthma, rash or gastrointestinal problems. There are no successful treatments known for GWS.
Sick Building Syndrome (SBS) is another disorder with multiple symptoms similar to GWS and perhaps Fibromyalgia/Chronic Fatigue Syndrome. It is of unknown etiology other than it occurs within certain buildings and produces allergic symptoms (skin rashes, asthmatic symptoms, and flu-like complaints), fatigue, cognitive problems, headaches, and muscle aches. It has been assumed that there is some form of allergen or toxic substance that affects those in the building involved, but no particular agent has been identified. There are no successful treatments for SBS other than leaving the building.
Opioid or narcotic abuse or addiction, most particularly addiction to or involving the abuse of heroin, but which also may involve other opiates such as propoxyphene, meperidine, hydromorphine, codeine, levorphanol, methadone, oxycodone, morphine, hydrocodone bitartrate and other opiate derivatives, represents a major drug problem throughout the world. It probably results from at least two events: (1) a chance or purposeful exposure of the addict or abuser to one of these opiates (either through illegal sources or medical sources) with the intake by oral, nasal, or intravenous routes, and (2) the individual exposed may have special needs for drugs which mute pain and distress. For instance, it is an infrequent event for patients to whom narcotics are administered for medical needs to develop dependence and addiction although they may show transient tolerance during treatment or withdrawal symptoms after cessation of the treatment. The binding sites in the brain and elsewhere of these opiate drugs are similar to the sites where our own endogenous pain-relieving endorphins and enkephalins bind. It has been proposed (E. J. Khantzian, Am. J. Psychiatry 142:1259-1264, 1985) that those who abuse narcotics as a drug of choice for dependence abuse or addiction are those who are subject to disorganizing and threatening affects of rage and aggression, perhaps from inadequate responses of their own endogenous pain-relieving endorphins. Many of these patients do not feel relief of pain over time the way most other people do. Treatment results for this serious addiction problem are extremely poor, mainly because of the lack of any non-addicting drug that can relieve the craving for narcotics in these addicts. Methadone treatment has been used commonly but methadone is just another addictive opiate which can be given conveniently in an oral form. Nevertheless, methadone is frequently abused and sold for abuse by addicts and others. There are no FDA-approved non-narcotic treatments for the chronic abuse of opiate narcotics.
Reflex Sympathetic Dystrophy Syndrome (RSDS), also called Complex Regional Pain Syndrome (CRPS), is a syndrome of pain, hyperesthesia, vasomotor disturbances, dystrophic changes, significant central nervous system, and cognitive central nervous system changes such as impaired short-term memory, disorganization, lack of concentration, and confusion. RSDS is a progressive disease of the autonomic nervous system that can follow trauma, a break or a fracture, a sharp force injury (such as a knife or bullet wound), heart problems, infections, surgery, or spinal injuries. About 5% of CRPS cases arise without apparent injury, known as xe2x80x9cspontaneousxe2x80x9d CRPS. RSDS is a multi-system disorder, most commonly found in women over the age of 50, which affects nerves, skin, muscles, blood vessels, bones and the central nervous system. RSDS affects extremities, the face, shoulders, back, and eyes. There are three stages of RSDS: the acute stage; the dystrophic stage; and the atrophic stage. These stages last around 6 months, but can vary in each individual. The acute stage has intense, severe constant, burning pain and neuralgia. The dystrophic stage includes, in addition to the symptoms of the acute stage, bone changes, hair and nail changes and rigidity and restrictive movement. In the atrophic stage, the pain spreads proximately, and irreversible tissue damage occurs. Severe restriction of function and anatomic dysfunction is experienced. Throughout the stages one experiences inflammation and extreme sensitivity to touch. The skin appears mottled, becomes easily bruised, and has a shiny red and tight look to it. There is often profuse sweating in the areas involved. Later in the course of the illness there is a constriction of the vasculature with coldness, loss of skin integrity, low-grade fever, edema, sores, dystonia, tremors, insomnia, emotional disturbance, memory problems, and demineralization of the bones in the affected limb. The treatments currently available aim at blocking the effects of sympathetic hyperactivity. The treatments address individual symptoms and offer temporary relief, such as physical therapy, non-steroidal anti-inflammatory drugs, tricyclic antidepressants, anticonvulsants, and corticosteroid injections. Some experimental treatments include Spinal cord stimulation, transcutaneous electrical nerve stimulation (TENS). There are no successful overall treatments other than narcotics or local anesthesia for the pain; or the recent use of baclofen which may temporarily relieve the dystonia. None of these treatments helps other multiple problems suffered by the RSDS patient.
Cerebral Palsy is a chronic disability characterized as a range of neuromuscular disorders caused by injury to an infant""s brain sustained during late pregnancy, birth or any time during the first two years of life. Approximately 2 per 1,000 individuals in the U.S. have cerebral palsy. Symptoms typically include reduced movement due to stiff or permanently contracted muscles; uncontrolled movements; difficulty with coordination while walking and moving the upper limbs, or inability to speak or swallow. Other associated problems include epilepsy, visual disturbances, hearing impairment, language difficulty, and slow growth. Causes which lead to Cerebral Palsy are typically prenatal causes such as infection, maternal stroke, exposure to environmental toxins, or brain development problems. Remaining causes are due to adverse events such as traumatic birth delivery, premature birth and complications, meningitis or head injury.
Sibutramine hydrochloride monohydrate (N,N-Dimethyl-1-[1-4-chlorophenyl cyclobutyl]-3-methylbutylamine hydrochloride monohydrate) available as MERIDIA(copyright) (Knoll Pharmaceutical Co., Mount Olive, N.J.) has been described for the treatment of obesity and depression (U.S. Pat. Nos. 4,746,680, 4,929,629 and 5,436,272), for diabetic hyperglycemia (WO 98/11884), and for hyperlipidemia (WO 98/13034). In contrast to many of the drugs mentioned above, sibutramine""s mode of action is believed to include, among other things, inhibition of serotonin, norepinephrine, and dopamine reuptake. Accordingly, it intensifies all three of these brain neurotransmitters at their post-synaptic receptor sites. These results are described, e.g., in U.S. Pat. No. 4,939,175 which also discloses the use of N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine to activate the central nervous system and thereby improve certain cerebral functions involved with memory such as senile dementia, amnestic syndrome, and learning, and to increase spontaneous movement as in Parkinson""s disease. There is no suggestion, however, to treat the neuropsychiatric symptoms and disorders treated according to the invention, i.e., neurological, behavioral and cognitive symptoms, particularly symptoms refractory to previous treatments.
It is an object of the invention to provide a treatment for severe secondary symptoms and disorders which often have not been successfully treated heretofore.
The invention provides a method of treating secondary neurological, behavioral, and cognitive symptoms or disorders emanating from primary organic impairments. The term neuropsychiatric will be used herein to encompass these neurological, behavioral and cognitive symptoms or disorders.
The conditions to be treated encompass symptoms and disorders including symptoms of Cerebral Palsy; symptoms of Torticollis; symptoms of Dystonia; symptoms of Dyskinesia, Lingual Dyskinesia or facial Dyskinesia, symptoms of Institutionalization Syndrome, Concentration Camp Syndrome or Survivor Syndrome; Dementia or chronic brain syndrome, Alzheimer""s-type Dementia or non-Alzheimer""s-type Dementia; symptoms of Sick Building Syndrome (SBS); symptoms of Gulf War Syndrome (GWS); symptoms of Reflex Sympathetic Dystrophy Syndrome (RSDS); symptoms of Retinitis Pigmentosa (RP); vocal and motor tics, obsessive compulsive behavior, and cognitive and behavior disorders of Tourette""s syndrome and non-Tourette""s disorders; symptoms of Posttraumatic Stress Disorder (PTSD); symptoms of multiple personality disorder; symptoms of Attention Deficit Hyperactivity Disorder (ADHD) or Attention Deficit Disorder (ADD); violence or rage such as seen with an intermittent explosive disorder; adult or adolescent sexual disorder or sexual dysfunction including hyposexuality, hypersexuality, obsessive-compulsive sexual activity, gender choice problems (including homosexuality), and sexual deviations (fetishism, transvestism, pedophilia, sadomasochistic behavior, exhibitionistic behavior, and frotteurism); self mutilation including self-laceration and other self-abuse; oscillopsia; psychological, behavioral, emotional, cognitive and motor symptoms of Huntington""s Disease; severe fatigue, sleep abnormalities, cognitive difficulties, and pain of fibromyalgia and chronic fatigue syndrome; severe psychoses with hallucinations and/or delusions refractory to conventional antipsychotic treatment as caused by primary impairments including trauma, brain tumors, amino acid imbalance, chromosomal abnormalities, metabolic disorders including renal failure and diabetes, and genetic disease; frontal lobe executive problems of forming appropriate plans and carrying them out in prompt fashion caused by various primary brain disorders; asocial behavior; and opiate narcotic dependency, abuse, or addiction. Patients advantageously treated have at least one of these symptoms or disorders.
The primary impairments which give rise to these symptoms include as non-limiting examples, temporal lobe epilepsy (TLE), Huntington""s Disease, Tourette""s Disorder, non-Tourette""s Disorder, atypical attention deficit disorder with or without hyperactivity, adult or adolescent sexual disorders, Posttraumatic Stress Disorder (PTSD), multiple personality disorder, borderline personality, and organic psychosis. The primary impairments can be systemic such as systemic lupus erythematosus; brain disorders from systemic causes such as metabolic, genetic or chromosomal diseases, brain cysts, and tumors; Fibromyalgia, Chronic Fatigue Syndrome; viral infections and resulting neurological injuries.
The treatment includes administering a pharmacologically effective dose of a dopamine, serotonin and norepinephrine reuptake inhibitor, particularly sibutramine, to a human in need of such treatment. The treatment has also been shown to interrupt endorphin-opioid pathology. Patients most advantageously treated are those with severe symptoms. By severe is meant intractable symptoms which have not responded to standard medication sufficiently to control those symptoms.
There are many secondary symptoms or disorders caused by or excited by various primary excitatory factors or impairments (diseases, illnesses, injuries, etc.). The primary impairments include brain impairments such as brain disease, brain lesions, and systemic impairments such as lupus erythematosus, fibromyalgia, and chronic fatigue syndrome.
It has been discovered that administration of sibutramine allows control of previously uncontrollable behavioral, cognitive, and neurological problems in patients suffering from a spectrum of neurological disorders. Clinical results show that symptoms successfully controlled include tics manifested by motor or vocal outbursts, episodic dyscontrol with anger and violence, self injury or mutilation, asocial behaviors, problems of executive (frontal lobe) function, severe posttraumatic stress disorder, panic outbursts, atypical psychoses with florid hallucinations and delusions refractory to previous treatments, the severe behavioral motor and psychotic symptoms of Huntington""s Disease (HD), atypical attention deficit disorder, sexual disorders, sleep problems, fatigue, cognitive dysfunction, or pain problems of fibromyalgia or chronic fatigue syndrome, and the opiate narcotic craving in opiate addiction.
Many of the disorders and symptoms are listed in The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) of the American Psychiatric Association, Wash., D.C.
The term sibutramine as used herein means compounds of sibutramine hydrochloride monohydrate, more specifically N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride preferably in its monohydrate form, and enantiomers and analogues thereof, as described in U.S. Pat. Nos. 4,746,680, 4,929,629 and 5,436,272. Sibutramine is believed to inhibit reuptake of norepinephrine, serotonin and dopamine thereby intensifying their effects in the brain. Sibutramine is commercially available as MERIDIA(copyright), Knoll Pharmaceutical Company, Mount Olive, N.J. Capsules are presently available with discrete dosages of 5, 10 and 15 mg for oral administration. The sibutramine is administered in a pharmaceutically active dose. The preferred dosage is about 5 mg three times a day but there is variation between patients for the best dose. It is believed that the cytochrome P450 system differs in individuals and the dose must be determined empirically in each patient. The effect of the cytochrome P450 system on metabolism of psychotropic drugs is discussed in xe2x80x9cIntercom: The Experts Conversexe2x80x9d, published by The Journal of Clinical Psychiatry, November 1995. The lowest effective dose has been shown to be 0.25 mg daily and the highest dose has been shown to be 45 mg (15 mg 3 times daily). It is possible that higher or lower doses can be used depending upon each individual. Therefore, more flexibility in available dosage is needed. Furthermore, means of administration such as injection, rectal suppository, or transdermal patches may be utilized. Finally, a long-acting slow-release means such as oral tablet or capsule would be the preferred route in view of the rapid metabolism noted (5 hour duration of action usually) in most of the patients.
The sibutramine, sibutramine salt or derivative thereof, is administered, preferably in a pharmaceutical carrier and in a pharmaceutically effective dose, preferably about 5 mg three times a day. The dose can vary depending upon the individual, e.g., from about 0.25 mg to 45 mg or more per day.
Although the use of sibutramine has been described for the treatment of conditions such as obesity, depression, diabetic hyperglycemia, hyperlipidemia, senile dementia and related conditions, and Parkinson""s disease, it has been discovered that sibutramine can be successfully used in treating other problems unrelated to these conditions. In treating other problems according to the invention, for example, rather than demonstrating an anti-obesity effect, most patients gained weight when the changes resulting from the method of the invention were taking place. For example, patients with ADD previously treated with stimulants found it easier to eat when treated with sibutramine and gained weight. Moreover, the improvements according to the invention were rapid and the symptoms were alleviated within minutes or hours of treatment. Therefore, the improvements were seen in the short term, and the improvements continued long term. In regard to depression, most of the patients treated were not clinically depressed and patients who were being treated with anti-depressants became depressed when removed from the anti-depressant medication and treated with sibutramine alone. It was generally necessary to continue anti-depressant therapy along with the sibutramine therapy.
It has been discovered that sibutramine acts as a stabilizer or normalizer of the secondary effects of various neuropsychiatric conditions. Sibutramine appears to correct multiple secondary, ancillary neurophysiological signs and symptoms of many neuropsychiatric disorders. While it is not intended to be bound by theory, this may be through a xe2x80x9cdampingxe2x80x9d neurological effect which would restrict or mute abnormal impulses emanating from the area of pathology or injury (such as the temporal lobe) to peripheral areas (such as the hypothalamus, the amygdala, the hippocampus, other limbic structures, or motor areas). Sibutramine is therefore usually an xe2x80x9cadd-onxe2x80x9d medication to other medications, such as antiepileptic or anti-depressant medications. It appears to be one of those very rare if not unique medicines that calms without sedating, activates without agitating, or, in sum, corrects these multiple severe neurophysiological problems toward normal. For many of the patients it also helps frontal lobe planning in executive function, thereby not only helping attention, but also intention.
Above and beyond the known effects of sibutramine on serotonin, dopamine and norepinephrine activation, there is believed to be an effect of this medication on the endorphic opiate neurotransmitter system which is evident in the patients who have been relieved of pain, rage, anger, self-mutilation and particularly addiction to heroin. Moreover, self-injury appears to activate the opioid system and the relief through sibutramine of the need to cut themselves in these patients strongly suggests endorphic involvement of some sort. It would appear that sibutramine activates endorphins or, at the very least, modifies the endorphinergic opioid systems to promote serenity and lack of pain and stress, and to reduce craving for heroin. Such a mechanism which was previously unsuspected may have also contributed to the therapeutic effects of sibutramine herein described for PTSD, asocial behavior and fibromyalgic pain which have not been helped by serotonin, dopamine and norepinephrine potentiators. This is in contradistinction to the therapeutic effects of sibutramine on ADHD, chronic fatigue, and the symptoms of Tourette""s and non-Tourette""s diseases. Finally, a differentiation between the serotonin, dopamine and norepinephrine potentiation versus the opiate-like therapeutic effects of sibutramine may be made in terms of duration of action, whereas the serotonin, dopamine, norepinephrine agonist effects lasted in most patients for only 4-6 hours (therefore requiring tid dosage), the opiate effects appear to last all day and require only a single AM dosage.
It has also been unexpectedly discovered that sibutramine promotes neurogenesis. Neurogenesis is the routine growth of new brain cells which is initiated by the chemical release of serotonin. Serotonin travels from one neuron to another by crossing a gap known as a synapse. Normally, once the receiving neuron is activated, the chemical is reabsorbed by the brain. Sibutramine was discovered to inhibit the reuptake of serotonin which allows serotonin to remain in the synapse and interact with its targets for much longer than it otherwise would. As a consequence, sibutramine can be administered as a means of promoting and/or controlling neurogenesis.
Neurogenesis has been found to be inhibited by the release of certain hormones, such as glucocorticoids. Studies have found that elevated levels of glucocorticiods, such as those found in depressed patients, actually suppress neurogenesis or even kill existing neurons, especially in the area of the hippocampus known as the dentate gyrus. Gary Greenberg, Discover, 65-68, July 2001. Thus, a lack of or decrease in neurogenesis, correlates with a decrease in size of the hippocampus, a region in the brain associated with learning, memory and emotion, and consequently, a decrease or inability for the patient to perform mental and physical activities associated with these skills.
The present invention has also found that patients with Post Traumatic Stress experienced inhibited neurogenesis, as shown by the shrinking hippocampus, due to the stress-induced release of glucocorticoids. Sibutramine not only relieved the symptoms of Post Traumatic Stress but it is believed that it induced neurogenesis, as evidenced by not only an increase in the hippocampus, but enhanced mental and motor skills associated therewith. These benefits were lost rapidly when either the patient was taken off sibutramine or when steroids, such as cortisone were concomitantly administered.
Furthermore, for most of these disorders, at this time there are no other known nor FDA approved medications currently available. The following nonlimiting examples illustrate the invention. In the following case histories, problems (symptoms or disorders) helped included:
1. Rage, violence, self-abuse. (Case Nos. 3, 47, 54, 97, 100, and 113)
2. Organically-based sexual dysfunction (including hyposexuality, obsessive-compulsive sexual preoccupation, and gender choice problems). (Case Nos. 20, 54, 77, 99, 100, and 109)
3. Severe post-traumatic stress disorder (PTSD). (Case No. 74)
4. The behavioral-emotional problems of Huntington""s Disease. (Case No. 113)
5. The cognitive and visual problems of Retinitis Pigmentosa (RP).
6. Oscillopsia associated with brain injury. (Case No. 111)
7. Treatment refractory Attention Deficit Disorder (ADHD) or (ADD) with or without hyperactivity. (Case Nos. 16, 20, 41, 47, 76, 77, 78, 100 and 109)
8. Tics, concentration problems, and behavioral problems of Tourette""s Disease. (Case Nos. 20 and 47) and non-Tourette""s Disease (Case No. 76).
9. Asocial behavior. (Case Nos. 20 and 54)
10. Severe atypical and neuroleptic refractory psychoses with delusions, hallucinations, and dyscontrol. (Case No. 97)
11. Enhancement of frontal lobe (executive planning) function (Case Nos. 41 and 78).
12. The fatigue, cognitive problems, sleep disorders, and pain of fibromyalgia, and chronic fatigue syndrome. (Case No. 141).
13. The symptoms due to Gulf War Syndrome (GWS).
14. The symptoms due to Sick Building Syndrome (SBS).
15. The craving for opiates in the dependent patient (case No. 165)
16. The symptoms due to Reflex Sympathetic Dystrophy Syndrome (RSDS), also known as Complex Regional Pain Syndrome (CRPS).
17. The symptoms due to Torticollis.
18. The symptoms due to Dystonia, Alzheimer""s-type and non-Alzheimer""s-type.
19. The symptoms due to Dyskinesia.
20. The symptoms due to Institutionalization Syndrome, also known as Concentration Camp Syndrome or Survivor Syndrome.
21. The symptoms due to Cerebral Palsy.
22. Motor skills disorders emanating from primary brain injury.
Some of the cases illustrate multiple problems.